Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mo....

In one survey one quarter of patients with Raynaud phenomenon not fitting the 1980 American College of Rheumatology classification criteria were reclassified as having systemic sclerosis using the 2013 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria.[1]

See Cutaneous Clues to Accurately Diagnosing Rheumatologic Disease, a Critical Images slideshow, to help recognize cutaneous manifestations of rheumatologic diseases.

Pathophysiology

Excessive collagen deposition causes skin and internal organ changes. Many factors, including environmental factors, can lead to immunologic system disturbances and vascular changes. Endothelial alterations may lead to a cascade of stimulatory changes that involve many cells, including fibroblasts, T lymphocytes, macrophages, and mast cells. In turn, the activated cells secrete a variety of substances, including cytokines and their soluble receptors and enzymes and their inhibitors. These substances lead to changes in the extracellular matrix compounds, including fibronectin; proteoglycans; and collagen types I, III, V, and VII. Increased collagen deposition in tissues is a characteristic feature of systemic sclerosis. Increased collagen production or disturbances in its degradation can cause excessive collagen deposition in tissues.

Fibrosis can be caused by profibrotic cytokines, including transforming growth factor-beta (TGF-beta), interleukin-4 (IL-4), platelet-derived growth factor (PDGF), and connective-tissue growth factor.[2] The vasculopathy may be linked to TGF-beta and PDGF, while the diminution of lesional cutaneous blood vessels can be attributed to antiendothelial cell autoantibodies. The activation of the immune system is of paramount importance in the pathogenesis of systemic sclerosis. Antigen-activated T cells, activated infiltrate early, infiltrate the skin, and produce the profibrotic cytokine IL-4. B cells may contribute to fibrosis, as deficiency of CD19, a B-cell transduction molecule, results in decreased fibrosis in animal models.

Different factors, including genetic, environmental, vascular, autoimmunologic, and microchimeric factors are involved in systemic sclerosis pathogenesis. One theory states that antigens from the human leukocyte antigen (HLA) histocompatability complex, including HLA-B8, HLA-DR5, HLA-DR3, HLA-DR52, and HLA-DQB2, are involved in systemic sclerosis. Some data suggest that apoptosis and the generation of free radicals may be involved in the pathogenesis of systemic sclerosis.

Epidemiology

Frequency

Systemic sclerosis is a rare disease. Systemic sclerosis is diagnosed in approximately 67 male patients and 265 female patients per 100,000 people each year.

International

Systemic sclerosis is estimated to occur in 2.3-10 people per 1 million. Systemic sclerosis is rare in the resident population of Japan and China.

Race

No apparent racial predominance exists. However, systemic sclerosis is rare in the resident population of Japan and China. Diffuse systemic sclerosis (dSSc) occurs more often in black women than in white women.

Sex

Overall, a substantial female predominance exists, with a female-to-male ratio of 3-6:1. However, dSSc occurs equally in males and females. The limited form of systemic sclerosis (lSSc) has a strong female predominance, with a female-to-male ratio of 10:1. Another analysis showed that men tend to have diffuse disease and women to have calcinosis.[3]

Age

Systemic sclerosis usually appears in women aged 30-40 years, and it occurs in slightly older men. In approximately 85% of cases, systemic sclerosis develops in individuals aged 20-60 years. Cases also are observed in children and in the elderly population.

Prognosis

The prognosis depends on the type of systemic sclerosis (SSc). In lSSc, a patient's condition can be stable for years. However, in dSSc, the disease can rapidly lead to death, if it is not treated promptly. Pulmonary hypertension may be an important cause of mortality in these patients. Survival complicated by pulmonary hypertension remains poor despite currently available treatment options.[4] Pulmonary hypertension was documented 25% of elderly patients, yet only in 12% of the youngest ones in a large study that stressed the differences in early- versus late-onset systemic sclerosis.[5] Cigarette smoking has been found to reduce overall survival.[6]

The undeniable impact of systemic sclerosis on quality of life underscores the need for a biopsychosocial approach to the clinical management. Orofacial manifestations need to be considered.[7] Timely detection of psychosocial difficulties and appropriate psychological or psychiatric intervention are also important steps toward better adherence to medical treatment.[8] Not surprisingly, the prevalence of depressive symptoms were evaluated as high and were independently associated with pain, fatigue, social support, emotion-focused coping, helplessness, and fear of progression.[9] Psychosocial factors associated with depressive symptoms merit attention.

A Canadian study assessed the World Health Organization Disability Assessment Schedule II (WHODAS II) as a valid measure of quality of life in systemic sclerosis patients. Results suggested the WHODAS II has good psychometric properties and is a valid measure of health-related quality of life in patients with systemic sclerosis.[10]

Mortality/morbidity

The mortality rate is increasing in the United States and Europe; as many as 3.08 persons are affected per 1 million. Generally, renal and lung changes are responsible for death in patients with systemic sclerosis. Pulmonary hypertension leads to 12% of systemic sclerosis–related deaths. Lung fibrosis and heart changes are responsible for 9% of systemic sclerosis–related deaths. These patients also have an increased risk of venous thromboembolism.[11]

History

Systemic sclerosis can have many different presentations. It involves the skin and many internal organs. Therefore, the presenting symptoms may differ among patients.

Cutaneous pruritus is common.

Raynaud phenomenon, or whitening of the hands on exposure to cold, is a common finding. Pain in the affected digits, blanching, cyanosis, and hyperemia can follow.

Difficulty in swallowing solid foods can be followed by difficulty with swallowing liquids and subsequent nausea, vomiting, weight loss, abdominal cramps, blotting diarrhea, and fecal incontinence.

The patient can have shortness of breath on exertion and, subsequently, at rest. Palpitations may occur without characteristic pain in thoracic cavity. The patient may have a nonproductive cough. Atypical chest pain, fatigue, dyspnea, and hypertension may be present.

Joint pain, limitation of movement, joint swelling, and muscle pain may be present. Systemic sclerosis begins as joint pain in 15% of patients. It begins as inflammatory myopathy in 10% of patients. Weakness is present in 80% of patients.

Medical signs and symptoms associated with disability, pain, and psychosocial adjustment in systemic sclerosis were assessed.[12] In one study, 114 patients underwent examination, including a determination of skin thickening. Signs and symptoms were a significant correlate of all outcomes. Patient-reported dependent edema significantly correlated with all outcomes. For disability, significant correlates were (1) physician-determined joint tenderness and number of tender points and (2) patient-reported joint pain with motion, joint contracture, extremity ulcers other than digital, and dyspnea.

Physical Examination

According to the American College of Rheumatology (ACR), features characteristic for scleroderma are divided into the following 2 groups (systemic sclerosis is diagnosed when a patient has 1 major and 2 minor criteria.):

Major features include centrally located skin sclerosis that affects the arms, face, and/or neck.

Minor features include sclerodactyly, erosions, atrophia of the fingertips, and bilateral lung fibrosis.

Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mo....

View Image

Puffy appearance of the woman's hand in the edematous phase of early scleroderma.

Systemic sclerosis is divided into 5 forms: (1) dSSc, (2) lSSc, (3) transitory form (dSSc/lSSc), (4) systemic scleroderma sine scleroderma, and (5) malignant scleroderma. The principal forms are dSSc and lSSc. In addition to the following features, dSSc is characterized by Raynaud phenomenon that precedes the development of skin changes by approximately 1 year:

Raynaud phenomenon of the hands: Symmetrical acral vasospasm is present, with characteristic pallor, cyanosis, suffusion, and a sense of fullness and ....

lSSc is characterized by sclerotic changes of the hands, face, feet, and forearms in addition to the following features (note the images below):

Atrophic changes of the ala nasi and lips, facial amimia

Telangiectasia of the skin

Late involvement of the lungs and late development of pulmonary hypertension

Anticentromere antibodies in approximately 70-80% of patients

Dilated capillary loops in nail folds: Either videocapillaroscopy or dermatoscopy can be used, with capillary dilatation, giant capillaries, and disrupted vascular configuration visualized.[18] Video capillaroscopy can be performed sequentially and may be useful to detect organ progression.[19] Dermatoscopy is efficient enough to delineate the pathognomonic alterations of the nailfold capillary pattern.

Cutaneous calcification: This finding varies and may rarely result in the rapid development of tumoral calcinosis.[20]

View Image

In systemic sclerosis, ulceration at the tip of the finger is regarded to be secondary to ischemia.

View Image

Hand of a woman with scleroderma of several years' duration: The thickened, tight, thin skin over the fingers is the result of self-amputation of the ....

dSSc and/or lSSc are described in a few cases in which internal organ changes preceded or simultaneously occurred with cutaneous changes.

Systemic scleroderma sine scleroderma is difficult to diagnose because only internal organs are involved. Systemic scleroderma sine scleroderma usually is diagnosed after the patient's death.

Malignant scleroderma most often occurs in men, usually in elderly men. An accelerated course of malignant scleroderma leads to death.

GI involvement can be serious.[21] Upper GI symptoms are generally more prominent than lower GI ones.

Pain is common those with systemic sclerosis and is independently associated with frequent episodes of Raynaud phenomenon, active ulcers, severe synovitis, and GI symptoms.[22]

Causes

Systemic sclerosis is an autoimmunologic disease, but the pathogenesis is only partially understood. Certain factors are well known to trigger occurrence of the disease or create a similar clinical appearance. Environmental factors include exposure to the following:

Drugs (eg, bleomycin, carbidopa, pentazocine, cocaine, penicillamine, vitamin K): A limited form of cutaneous systemic sclerosis has been described with paclitaxel in with the setting of breast cancer.[15]

Appetite suppressants (eg, phenylethylamine derivatives)

Substances used in cosmetic procedures (eg, silicone or paraffin implants)

Complications

Neoplastic diseases may complicate the disease course. Examples include breast carcinoma; multiple myeloma; lymphoma; and cancer of the ovary, esophagus, colon, or rectum.

Female patients should be evaluated for breast cancer. Epidemiologic studies have suggested that patients with scleroderma have an increased risk of cancer. However, large-scale case-control studies are needed to substantiate a possible association between scleroderma—both cutaneous and systemic—and breast cancer.[23]

Increased urea and creatinine levels in patients with kidney involvement

C-reactive protein: The nonspecific inflammatory marker C-reactive protein was found elevated in about one quarter of patients with systemic sclerosis, especially early disease, in whom it correlated with disease activity, severity, poor pulmonary function, and shorter survival.[27]

Imaging Studies

Chest radiographs may show normal findings in 5-10% of the patients, even when the patients have respiratory tract symptoms. In approximately 30-60% of patients, fibrosis of the basal parts of the lungs is observed. Occasionally, pictures of diffuse ground-glass and honeycomb lung patterns are observed. In patients with honeycomb lung patterns, changes are irreversible. These changes can be an important feature of patient's response to treatment.

Bone radiography reveals generalized osteopenia, which most commonly affects the hands. Intra-articular calcifications often are observed.

Gastrointestinal tract changes may be depicted. Scintigraphy of the esophagus may reveal a disturbance of the esophageal passage.[28] Manometric esophageal changes may be observed during invasive examination. Upper gastrointestinal tract evaluation should be performed only in systemic sclerosis, but not in morphea.[29]

Cardiac and pulmonary vascular involvement in systemic sclerosis should be evaluated. Cardiac abnormalities may be assessed by Doppler echocardiography.[30] Left- and right-sided heart diseases were found to be common in persons with systemic sclerosis. A few patients had a restrictive mitral flow pattern, possibly due to primary cardiac involvement of systemic sclerosis. Diastolic dysfunction is the most common cardiac finding.[31]

Because cardiac involvement is one of the major problems in systemic sclerosis, evaluation of ventricular function using echocardiographic strain imaging should be considered, because it appears to be useful to detect subclinical cardiac involvement in systemic sclerosis patients with normal standard echocardiographic and tissue Doppler velocity findings.[32]

Since the initial changes in systemic sclerosis are believed to involve microcirculation, its evaluation using laser Doppler flowmetry in the distal portion of the upper extremity has been advocated.[33]

Other Tests

With bronchoalveolar lavage (BAL), abnormal numbers of granulocytes, particularly neutrophils and eosinophils are present in BAL fluid. In addition, the concentration of vascular endothelial growth factor may be low.[34]

The gas transfer measurement (KCO), adjusted for alveolar volume, is also reduced.

Heart changes, including myocardial disease, pericardial problems, conduction system disease, and arrhythmias, can be observed with the following tests:

Electrocardiography (ECG)

Holter 24-hour monitoring

Doppler ultrasonography (US)

Exophthalmos, macroglossia, and/or gigantism may be present, with increased polyphasic potentials of normal or decreased amplitude.

Antihistone antibodies can be observed in the course of systemic sclerosis, but they are not characteristic. The following antinuclear antibodies (ANAs) are characteristic of scleroderma:

Antibodies against topoisomerase I DNA (Scl 70) are detected in the serum of patients with systemic sclerosis. The antibodies are detected in two thirds of patients with dSSc and interstitial lung fibrosis.

Anticentromere antibodies (ACAs) are most commonly detected in patients with lSSc; in these patients, changes in the heart, kidneys, and lungs (without fibrosis) are observed less frequently than in other patients.

ANAs can be detected in the course of systemic sclerosis. ANAs include antibodies against fibrillarin, a 34-kd protein of ribonucleoprotein U3 RNP; antibodies against the ribonucleoprotein nucleolar 7-2 RNA protein particle Th RNP; and antibodies to 20-110-kd proteins related to preribosomes (PM-Scl). Anti-PM/Scl antibodies are seen in roughly 24% of patients with polymyositis/systemic sclerosis overlap syndrome. They are also found in 3-10% of systemic sclerosis patients.[35, 36] The spectrum of systemic sclerosis-associated ANA differs in patients with and without cutaneous involvement.[37] ANA serum levels in patients with systemic sclerosis are not correlated with disease activity.

Elevated high-sensitivity C-reactive protein appears related to the occurrence of antimitochondrial antibody in these patients.[38]

With capillary microscopy, enlarged capillaries are observed in all 3 portions of the capillary nail fold–arterial, apical, and venous– and especially at the edge of the nail fold. Adjacent areas are avascular.

Spirometry demonstrates functional lung disturbances. In approximately 70% of patients, the DLCO is decreased.

Histologic Findings

In the active indurative phase, a loss of rete ridges occurs, epidermal skin appendages atrophy, and collagen fibers in the reticular dermis appear broad and hyalinized. A loss of space between collagen bundles is noted. Mononuclear cells, mostly T cells, form a variable perivascular infiltrate in the deep dermis and subcutis. Later, sclerotic changes predominate. The number of adnexal structures is reduced, and a loss of periadnexal fat is noted.

In one study, progressive systemic sclerosis histologic changes were systematically scored in skin biopsy specimens of dorsal forearm and upper inner arm in 53 consecutive patients and controls. The amount of hyalinized collagen, myofibroblasts, mean epidermal thickness, the mononuclear cellular infiltration, and the frequency of focal exocytosis varied significantly between those with and those without local clinical skin involvement.[39]

Medical Care

Different treatment regimens for systemic sclerosis exist. The therapeutic approach depends on the presentation of the disease and complexity of symptoms. In a recent review of the literature, calcium channel blockers, prostanoids, tadalafil, and bosentan received the strongest recommendations for their effectiveness for Raynaud phenomenon and digital ulcers.[40]

In pruritus, the following agents are sometimes helpful:

Camphor and menthol

Topical emollients

Psoralen UV-A (PUVA) treatment

UVA-1 phototherapy

In patients with calcinosis, surgery may be of some benefit, but healing time is often prolonged.

When Raynaud phenomenon is present, the most effective nonpharmacologic method of preventing Raynaud episodes is avoiding exposure to cold temperature and wearing layers of warm, loose-fitting clothing, including socks and gloves. Also, smoking cessation is advised. In the pharmacologic regimen, consider the use of agents such as calcium-channel blockers, vasodilating drugs, intravenous prostaglandins, prostacyclin analogs, or aspirin.[41]

In patients with kidney involvement, ACE or angiotensin II inhibitor therapy is indicated.

In patients with GI tract involvement, proton pump inhibitors (eg, omeprazole) and H2 blockers can help to control reflux symptoms.

In patients with lung involvement, calcium-channel blockers (eg, nifedipine), prostaglandins (eg, prostacyclin), and cyclophosphamide have been used with variable success. When inflammatory myositis is present, the use of high doses of corticosteroids (eg, prednisolone with a starting dose of 1 mg/kg/d) is suggested.

Antifibrotic agents have been investigated, although results have varied and none is clearly shown to be of consistent benefit. These have included D-penicillamine, interferon alfa and interferon gamma, and immunomodulatory agents. Immunomodulatory agents have included the following:

Surgical Care

The cutaneous telangiectasias can be treated. The number of pulsed dye laser treatments required to effectively clear systemic sclerosis/CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome telangiectasia was approximately 2-fold higher than with sporadic telangiectasias, a finding attributed to thickened collagen fibers and blood vessels.[54] Pulsed dye laser (PDL) and intense pulsed light (IPL) may be used, both being effective, although the former produces a better cosmetic result but with more adverse effects than the latter.[55]

Medication Summary

Treatment regimens have enormous diversity. Currently, no standard therapy is available for skin sclerosis. Raynaud phenomenon often responds to calcium channel blockers, and scleroderma kidney disease often responds to angiotensin-converting enzyme and angiotensin II inhibitors. The treatment depends on the presentation of systemic sclerosis. The efficacy and safety of lidocaine in treating scleroderma has been questions, with an analysis showing a lack of efficacy.[56]

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Clinical Context:
Prednisone is an immunosuppressant used for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Tacrolimus (Prograf)

Cyclophosphamide (Neosar, Cytoxan)

Clinical Context:
Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve DNA cross-linking, which may interfere with the growth of healthy and neoplastic cells.

Aspirin (Bayer Buffered Aspirin, Bayer Aspirin, Anacin)

Clinical Context:
Aspirin inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. It may be used in low doses to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Class Summary

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Biogen/IDEC (Discussion of Drug reactions in relationship to an agent for Multiple Sclerosis)<br/>Received income in an amount equal to or greater than $250 from: Abbvie; Lilly; Argenx; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mouth is also characteristic in the later stage of the disease.

Face of 65-year old woman with systemic sclerosis and skin thickening of 20 years' duration: Note the pinched nose, taut skin with numerous telangiectasias, and retraction of the lips.

Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mouth is also characteristic in the later stage of the disease.

Puffy appearance of the woman's hand in the edematous phase of early scleroderma.

In systemic sclerosis, skin hyperpigmentation of the lower legs is surrounded by areas of hypopigmentation. The result is a salt-and-pepper appearance.

Raynaud phenomenon of the hands: Symmetrical acral vasospasm is present, with characteristic pallor, cyanosis, suffusion, and a sense of fullness and tautness.

In systemic sclerosis, ulceration at the tip of the finger is regarded to be secondary to ischemia.

Hand of a woman with scleroderma of several years' duration: The thickened, tight, thin skin over the fingers is the result of self-amputation of the distal phalanx due to ischemia. Moderately severe flexion contractures of the fingers are present.

Face of 65-year old woman with systemic sclerosis and skin thickening of 20 years' duration: Note the pinched nose, taut skin with numerous telangiectasias, and retraction of the lips.

Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mouth is also characteristic in the later stage of the disease.

Raynaud phenomenon of the hands: Symmetrical acral vasospasm is present, with characteristic pallor, cyanosis, suffusion, and a sense of fullness and tautness.

Puffy appearance of the woman's hand in the edematous phase of early scleroderma.

In systemic sclerosis, ulceration at the tip of the finger is regarded to be secondary to ischemia.

Hand of a woman with scleroderma of several years' duration: The thickened, tight, thin skin over the fingers is the result of self-amputation of the distal phalanx due to ischemia. Moderately severe flexion contractures of the fingers are present.

In systemic sclerosis, skin hyperpigmentation of the lower legs is surrounded by areas of hypopigmentation. The result is a salt-and-pepper appearance.